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Alteration of the p53 Gene in Human Primary Cervical Carcinoma with and without Human Papillomavirus Infection

Departments of Obstetrics and Gynecology [M. F., M. I., O. T.] and Radiation Biology [T. E.], Osaka University Medical School, 2-2, Yamadaoka, Suita, Osaka 565, and Kanebo Institute for Cancer Research, 9-1, Misakicho-1-chome, Hyogo-ku, Kobe 652, Japan [S. I.]

A previous report using cervical carcinoma cell lines suggests that the inactivation of two tumor suppressor gene products, p53 and pRB, either by complex formation with the E₆ and E₇ proteins of oncogenic human papillomaviruses (HPVs) or by mutation, may be an important step in cervical carcinogenesis (M. Scheffner et al., Proc. Natl. Acad. Sci. USA, 88: 5523–5527, 1991). The present study was designed to clarify the association between p53 inactivation and infection with oncogenic HPVs in primary carcinomas of human uterine cervix. We examined 36 primary cervical carcinomas for the presence of HPV DNAs by Southern blot analysis with probes specific for HPV-16, -18, -31, -33, -52, -56, and -58. HPV DNA sequences were detected in 19 of 36 tumors: 10 cases with HPV-16; 3 cases with -18; 3 cases with -58; 2 cases with -56; and one case with -52. The presence of HPV-16 and -18 in cervical carcinomas was further reexamined using polymerase chain reaction. HPV DNA sequences were detected in an additional 10 cases: 9 cases with -16 and one case with -18. The inactivation of the p53 gene by allelic loss or by point mutation was also examined. No allelic loss at the polymorphic site in codon 72 of the p53 gene was detected in any of 10 informative cases. Missense point mutations in the highly conserved regions of the p53 gene were demonstrable as single-stranded conformational polymorphisms of polymerase chain reaction-amplified DNA fragments and subsequently identified by direct DNA sequencing. Point mutations were detected in only two cases: one with an ATGCTG transversion in codon 133 of exon 5, resulting in a MetLeu substitution, and another with a CGGTGG transition in codon 248 of exon 7, resulting in an ArgTrp substitution. Both tumors with point mutations in p53 genes were among 10 tumors which contained a small copy number of HPV-16 DNA sequences (1 copy of HPV/10¹ to 10⁵ cells) detectable by polymerase chain reaction amplification but not by Southern blot analysis of genomic DNAs derived from the tumors. None of 19 tumors with a large copy number of HPV DNA sequences detectable by Southern blot analysis (more than 1 copy of HPV/2 to 10 cells) nor any of 7 tumors with undetectable HPV DNA sequences contained p53 gene mutations in the regions examined. These observations suggest that, in contrast to data derived from cultured cervical carcinoma cell lines, inactivation of the p53 gene by allelic loss or by point mutation is infrequent in clinical samples of cervical carcinomas of the human uterus, irrespective of the presence or absence of HPV infection.

¹ To whom requests for reprints should be addressed.

Received 4/27/92. Accepted 7/20/92.

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